Neurocrit Care

https://doi.org/10.1007/s12028-019-00829-x

VIEWPOINT

High‑Dose Intravenous Ascorbic Acid: Ready

for Prime Time in Traumatic Brain Injury?
Stefan W. Leichtle1*  , Anand K. Sarma2, Micheal Strein3, Vishal Yajnik4, Dennis Rivet5, Adam Sima6
and Gretchen M. Brophy3,5

© 2019 Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society

Abstract 
Traumatic brain injury (TBI) is one of the leading public health problems in the USA and worldwide. It is the num-
ber one cause of death and disability in children and adults between ages 1–44. Despite efforts to prevent TBIs, the
incidence continues to rise. Secondary brain injury occurs in the first hours and days after the initial impact and is
the most effective target for intervention. Inflammatory processes and oxidative stress play an important role in the
pathomechanism of TBI and are exacerbated by impaired endogenous defense mechanisms, including depletion of
antioxidants. As a reducing agent, free radical scavenger, and co-factor in numerous biosynthetic reactions, ascorbic
acid (AA, vitamin C) is an essential nutrient that rapidly becomes depleted in states of critical illness. The administra-
tion of high-dose intravenous (IV) AA has demonstrated benefits in numerous preclinical models in the areas of
trauma, critical care, wound healing, and hematology. A safe and inexpensive treatment, high-dose IV AA adminis-
tration gained recent attention in studies demonstrating an associated mortality reduction in septic shock patients.
High-quality data on the effects of high-dose IV AA on TBI are lacking. Historic data in a small number of patients
demonstrate acute and profound AA deficiency in patients with central nervous system pathology, particularly TBI,
and a strong correlation between low AA concentrations and poor outcomes. While replenishing deficient AA stores
in TBI patients should improve the brain’s ability to tolerate oxidative stress, high-dose IV AA may prove an effective
strategy to prevent or mitigate secondary brain injury due to its ability to impede lipid peroxidation, scavenge reac-
tive oxygen species, suppress inflammatory mediators, stabilize the endothelium, and reduce brain edema. The exist-
ing preclinical data and limited clinical data suggest that high-dose IV AA may be effective in lowering oxidative stress
and decreasing cerebral edema. Whether this translates into improved clinical outcomes will depend on identifying
the ideal target patient population and possible treatment combinations, factors that need to be evaluated in future
clinical studies. With its excellent safety profile and low cost, high-dose IV AA is ready to be evaluated in the early
treatment of TBI patients to mitigate secondary brain injury and improve outcomes.
Keywords:  Traumatic brain injury, Secondary brain injury, Oxidative stress, Antioxidant, Free radical scavenger,
Vitamin C, Ascorbic acid

*Correspondence: stefan.leichtle@vcuhealth.org
1
Division of Acute Care Surgical Services, Department of Surgery, Virginia
Commonwealth University School of Medicine, Richmond, USA
Full list of author information is available at the end of the article
Traumatic Brain Injury
Traumatic brain injury (TBI) is one of the leading pub-
lic health problems in the USA and worldwide, result-
ing in 2.8 million Emergency Department (ED) visits
and 56,000 deaths per year [1]. Already the leading cause
of death and disability in children and adults between
ages 1–44, the incidence of TBI continues to rise [1].
In addition to the direct brain injury caused by trau-
matic impact, secondary brain injury due to local tissue
ischemia, edema, metabolic changes, and damage from
reactive oxygen species (ROS) results in further neuro-
logic deterioration [2-10]. Current treatment strategies to
mitigate secondary brain injury are limited to the optimi-
zation of a patient’s general clinical condition, including
maintenance of adequate cerebral perfusion pressures,
management of intracranial hypertension, and preven-
tion of hypotension, hypoxia, and seizures. No proven,
effective treatment exists to provide neuroprotection in
the acute phase or to promote neuroregeneration in the
delayed therapeutic window after TBI [11, 12].
Ascorbic Acid (Vitamin C)
Ascorbic acid (AA, vitamin C) is an essential nutrient
that functions as an important reducing agent, free radi-
cal scavenger, and co-factor in numerous biosynthetic
reactions [13-15]. The recommended dietary allow-
ance for AA for healthy individuals is 75 mg and 90 mg
per day for women and men, respectively, though some
guidelines recommend higher doses of up to 200 mg per
day [16]. AA is readily absorbed from the intestinal tract
when consumed orally, and higher doses above 1000 mg
per day are excreted renally [17, 18]. While oral adminis-
tration of AA is adequate to maintain homeostasis, intake
of substantially higher doses is required to achieve supra-
normal, ROS-scavenging AA concentrations, particularly
in states of acute injury and critical illness [18, 19].
While not universally defined, normal AA concentra-
tions range from 21 μmol/L (0.37 mg/dL) to 100 μmol/L
(1.76  mg/dL) [17, 20, 21]. In a small cohort of healthy
volunteers, mean peak plasma concentrations of AA
reached 134.8  ±  20.6  μmol/L after oral administra-
tion of 1250  mg AA. In contrast, IV administration of
this dose resulted in peak plasma concentrations of
885 ± 201.2  μmol/L. Predicted maximum peak plasma
concentrations were no more than 220 μmol/L with oral
administration of 3000  mg AA every 4  h, but reached
1760  μmol/L for IV administration of this dose [22].
Based on these and other data, any effective AA treat-
ment regimen for critically ill patients must be admin-
istered IV rather than orally. In 20 critically ill patients
with multiple organ dysfunction, 2000  mg AA per day
given IV restored normal AA plasma concentrations, but
only a daily dose of 10,000 mg IV AA elevated plasma AA
concentrations to above 1000  μmol/L, the optimal con-
centration for free radical scavenging effects [20, 22-24].
In 24 critically ill patients with sepsis, Fowler et al. dem-
onstrated that IV administration of 200 mg/kg per day (as
compared to 50 mg/kg/d) in four bolus doses effectively
and consistently elevated steady-state plasma concentra-
tions to above 1000 μmol/L within 24 h of the first dose
[23]. Therefore, a treatment regimen of 50 mg/kg IV AA
given every 6 h (for a total of 200 mg/kg per day) is most
likely to result in consistently supra-normal, ROS-scav-
enging plasma AA concentrations in critically ill patients.
In its oxidized form dehydroascorbic acid (DHA), AA is
actively and preferentially transported into the central
nervous system (CNS), crossing the blood–brain barrier
(BBB) by facilitative transport. This mechanism results
in substantially higher AA concentrations in the CNS
than in plasma [25, 26]. Therefore, plasma concentrations
of AA may not be reflective of CNS concentrations, but
their correlation is unclear.
AA administration has few clinically relevant adverse
effects. As a highly water-soluble compound, AA is
readily excreted through kidneys and urine, limiting the
potential for systemic toxicity. Therefore, direct renal
toxicity and formation of oxalate stones is the most fre-
quently noted concern with high-dose AA treatment [27].
Healthy individuals did not experience relevant adverse
effects or laboratory abnormalities with daily doses of
7500 mg IV for 6 days [28], critically ill patients tolerated
daily administration of 4500 mg IV for 28 days [29], and
even higher doses were found to be safe in phase-1 can-
cer and sepsis trials [23, 30-32]. Occasionally reported
adverse effects include gastrointestinal discomfort and
headache, but overall, high-dose IV AA is regarded to
have a good safety profile with a low risk of toxicity over a
wide range of doses.
Ascorbic Acid Deficiency in Critical Illness, Trauma,
and Burns
Critical illness is marked by depletion of AA stores [33-
35]. The administration of antioxidants, including AA,
in states of critical illness has re-emerged as a promising
area for study due to significant success in small patient
cohorts with septic shock [23, 36] and supported by basic
science research in trauma, wound healing, and hema-
tology [37-40]. Traumatic injuries, acute infection, and
critical illness result in a pro-inflammatory state marked
by dysregulation of the immune system, high levels of
ROS, and capillary leak due to endothelial damage and
increased permeability [41-43]. Antioxidants, most
importantly AA, have the potential to influence these
pathomechanisms.
In rodent models of bacterial- or endotoxin-induced
sepsis, AA administration attenuated the inflammatory
response and decreased microvascular permeability,
decreasing their risk for organ dysfunction and mitigating
lung damage [44, 45]. Clinically, lung-protective effects of
AA were described by Nathens et al. [29] in a cohort of
severely injured trauma patients in the ICU setting. IV
administration of 1000 mg AA three times per day, enter-
ally supplemented by 1000 IU alpha-tocopherol, resulted
in modest but significant reduction of pulmonary com-
plications. Berger and colleagues studied a mix of antiox-
idant supplements (2700  mg AA per day, and selenium,
zinc, and vitamin B1) in a randomized trial involving a
heterogenous surgical population of 200 patients, 30%
of which were trauma patients. This antioxidant cocktail
reduced C-reactive protein (CRP) concentrations, but
had no measurable effect on organ dysfunction [46].
In a porcine model of severe polytrauma and hemor-
rhage, Reynolds et al. demonstrated that AA supplemen-
tation mitigated end-organ damage on histopathologic
assessment, severity of lung injury, and decreased levels
of the pro-inflammatory markers interleukin (IL)-1β,
IL-8, TNFα, plasminogen activator inhibitor-1, and tissue
factor [37]. While similar effects have been corroborated
in numerous prior small animal studies, there are no con-
clusive data from clinical trials in (poly)trauma patients.
In animal and clinical studies of severe burn injuries, AA
administration decreases capillary leak and significantly
reduces resuscitation fluid requirements [47-49]. Doses
evaluated ranged from 15  mg/kg/h in animal studies to
66  mg/kg/h in clinical trials. Similar to other fields of
study, animal studies far outnumber clinical trials, and
results in the clinical setting are less impressive than in
animal models.
Ascorbic Acid in TBI
Oxidative stress is an important contributor in the patho-
genesis of secondary brain injury [2, 4-10]. Cellular
defense mechanisms against this damage are impaired
Fig. 1  Proposed reactive oxygen-scavenging-mechanism of high-dose IV ascorbic acid in TBI. TBI, traumatic brain injury; O
cies; DNA, deoxyribonucleic acid
in acute illness due to the depletion of free radical scav-
engers such as AA [7, 8, 34, 50, 51]. Figure 1 shows one
of the proposed mechanisms of neuroprotection of high-
dose IV AA in TBI. In a small cohort of patients with
TBI and hemorrhagic stroke, plasma concentrations of
AA were found to be low and inversely correlated with
injury severity. In this 2001 study, 13 patients with TBI
had significantly lower plasma concentrations of AA
(29 ± 8  μmol/L) than healthy controls (52 ± 8  μmol/L),
and AA plasma concentrations inversely correlated with
hemorrhage size [34]. In a 1984 study of AA concentra-
tions in the cerebrospinal fluid (CSF) of 41 patients with
neurologic disorders, five patients with TBI had lower
AA concentrations than all other patients, including
those with hydrocephalus and seizure disorders. AA con-
centrations in the CSF of patients with head and cervical
trauma were 77 ± 56  μmol/L compared to the reference
cohort with an average of 203 ± 49 μmol/L [7].
These few clinical studies on AA deficiency in patients
with TBI are in contrast to more robust literature in ani-
mal models. In rodent models of ischemic stroke, DHA
exhibited neuroprotective effects in both pre-treated
animals and those that received DHA after the ischemic
insult [52, 53]. In a rodent model of TBI, combined
administration of moderate doses of AA and vitamin E
resulted in improved cellular defense mechanism and
confirmed depletion of important antioxidants after TBI
[54]. In a rodent model of spinal cord injury, high-dose
AA administration significantly reduced tissue necrosis
and improved functional performance in rats [55].
In addition to its potent action as free radical scav-
enger, AA may stabilize the endothelium and pro-
mote integrity of the BBB. Following the mechanical
impact of TBI, ischemia, reperfusion, and the imbal-
ance between diminished protective factors such as
free radical scavengers and NF-E2 related factor-2
[56, 57] and upregulated damaging factors such as
­ 2−, reactive oxygen spe-
metalloproteinase (MMP)-9 lead to disruption of trans-
membrane tight junction proteins in the basal lamina
of the BBB [55, 56, 58-61]. ROS cause cell damage
through lipid peroxidation of the fatty acids in cell and
mitochondrial membranes [62, 63]. With its potent
antioxidant properties, high-dose AA may mitigate this
cascade [57, 61].
Unfortunately, clinical data on the therapeutic use of
antioxidants to date have been inconclusive or disap-
pointing [64]. Strategies that showed promise in animal
models and preclinical testing such as mitochondrial
protection, progesterone administration, anticonvul-
sants, and several antioxidant strategies like resveratrol,
flavonoids, and omega-3 polyunsaturated fatty acids have
not translated into successful clinical trials [65-68]. Com-
pared to other states of critical illness, there is a paucity of
data on the clinical use of AA in TBI. Table 1 provides an
overview of studies on AA in patients with critical illness
in the last two decades, fewer than 10% of which included
patients with severe TBI. In the only randomized con-
trolled trial on AA in TBI, high-dose (10,000 mg  days 1
and 4; 4000 mg days 5 through 7) IV AA administration
in 23 patients resulted in decreased perilesional edema
on CT imaging (p = 0.01), but no improvement in out-
comes [69]. Due to the dosing regimen, it is unlikely that
ROS-scavenging plasma levels were reached in this trial.
The most appropriate dose of AA in TBI is not known.
However, higher doses have shown benefit in other criti-
cally ill patients without causing harm. Therefore, mod-
erate to high doses of IV AA (10,000–20,000  mg per
day) may be required to replenish deficient AA stores in
patients with TBI experiencing oxidative stress several
days after injury. Due to the limited data on prevalence
and extent of AA deficiency in TBI, it is unclear if and
to what degree this would translate into protection from
secondary brain injury and improved clinical outcomes.
Contemporary data on AA concentrations in plasma and
CSF of patients with varying degrees of TBI may allow for
the identification of a high-risk patient population that
would benefit most from AA repletion and is currently
being studied by our research group. Based on animal
data [70, 71], the aging brain may be particularly suscep-
tible to oxidative damage due to an inability to take up
and mobilize AA. Clinically, lower CNS/plasma AA ratio
in older adults compared to younger patients with TBI
may indicate a high-risk patient group for further study.
Administration of high-dose IV AA (≥ 200  mg/kg per
day) would harness the anti-inflammatory, ROS-scav-
enging, and cell membrane-stabilizing properties of AA.
These mechanisms of action may be most beneficial in
patients with significant cerebral edema and elevated
intracranial pressure when administered within hours

Table 1  Pertinent clinical trials of IV ascorbic acid in the last two decades
References Design Type of injury Patients ­ osinga Results
Ascorbic acid d

Marik et al. 2017 [36] Retrospective before- Severe sepsis/septic 94 adults 6 g ×  4 ­daysb Mortality reduction
after shock
Fowler et al. 2014 [23] Randomized double- Severe sepsis (mostly 24 adults 50 mg/kg/day Reduced SOFA scores
blind placebo- respiratory) or 200 mg/kg/ and inflammatory
controlled day × 4 days markers
Razmkon et al. 2011 Randomized double- TBI with GCS ≤ 8 100 adults (four 10 g in day 1, 10 g on High-dose AA decreased
[69] blind placebo- groups, 23 patients day 4, 4 g daily for perilesional edema on
controlled received high-dose three more ­daysb head CT
AA)
Barbosa et al. 2009 [49] Randomized double- Burns with TBSA 32 children Up to 2.7 g ­dailyb Decreased lipid per-
blind placebo- 10-50%, at least (1.5 × upper daily oxidation and faster
controlled partial thickness intake based on age) wound healing
for 5 days
Berger 2008 [18] Randomized double- Complex cardiac sur- 200 adults (21 with 2.7 g for two days, 1.6 g Decreased inflammatory
blind placebo- gery, major trauma, SAH) for three ­daysb response (CRP)
controlled or SAH
Nathens et al. 2002 [29] Randomized prospec- Trauma patients, 595 patients 1 g TID for up to Decreased risk for MSOF,
tive trial excluding isolated 28 days or length of shorter ICU stay
TBI and patients with ICU ­stayb
GCS ≤ 6
Tanaka et al. 2000 [47] Randomized prospec- Burns with TBSA ≥ 20% 37 adults 66 mg/kg/hr as Decreased IVF require-
tive trial continuous infusion ments and improved
for 24 h respiratory function
CRP C-reactive protein, CT computed tomography, GCS Glasgow Coma Scale, IVF intravenous fluid, MSOF multi-system organ failure, SAH subarachnoid hemorrhage,
SOFA sequential organ failure assessment, TBI traumatic brain injury, TBSA total body surface area
a
  Only AA dosing shown
b
  AA was part of a treatment regimen including other medications
of TBI. Many animal studies that examined the admin-
istration of antioxidant cocktails and vitamins, includ-
ing AA, did not employ such high doses. However, these
higher doses are required in critically ill patients to reli-
ably achieve protective antioxidant concentrations and
beneficial clinical outcomes, as recently demonstrated in
patients with septic shock [23, 36].
Prehospital administration of IV AA to patients with
(suspected) TBI could be even more effective in mitigat-
ing damage to the blood–brain barrier and mitochondria
of the brain parenchyma, which starts to occur within
minutes of the traumatic event [62, 63]. However, pre-
hospital administration of AA would add substantial
complexity to a clinical trial; challenges would include
the correct identification of TBI as the cause for altered
mental status in (poly-)trauma patients, the possible
lack of knowledge of comorbidities that could increase
the risk profile of high-dose AA administration, and the
logistical challenge of storing solutions of high-dose AA
on ambulances. For the latter, promising data exist on
the stability of solutions containing low- to moderate AA
doses [72]. If results of a solid clinical (in-hospital) trial
indicate therapeutic efficacy of AA in TBI, studies on the
prehospital administration of AA for TBI in select patient
populations should certainly be considered.
Limitations and Challenges
Primary TBI and ROS-mediated damage to brain paren-
chyma and the BBB occur at the time of injury and
shortly thereafter [62, 63], making administration of neu-
roprotective agents challenging. Even in mature trauma
systems, the first dose of AA may realistically not occur
until hours after injury rather than minutes after the ini-
tial traumatic event as in preclinical models. Therefore,
the effect of high-dose AA will likely be of particular ben-
efit in those with areas of substantial ischemic penum-
bra, cerebral edema, and elevated intracranial pressure.
Additional benefit would be expected from the general
effect of high-dose AA on the state of TBI-related critical
illness.
In rodent models of TBI, the oxidized form of AA,
DHA, is more effective in crossing the BBB [52] and con-
centration-dependent downregulation of AA transport-
ers across the BBB might impede the accumulation of
supra-normal, ROS-scavenging concentrations of AA in
the CNS [73]. DHA is not currently FDA-approved and
is only used in experimental models. However, the AA
plasma concentrations that can be achieved with high-
dose IV administration will provide a steep plasma con-
centration gradient [74] ensuring uptake into the CNS.
Lastly, both continuous and intermittent administration
regimens of AA may need to be examined. In Fowler
et al.’s phase I study on high-dose IV AA in patients with
sepsis, doses of 200  mg/kg per day, given in four doses
every 6  h, rapidly led to plasma AA concentrations of
≥ 1000  μmol/L [23]. In de Grooth et  al.’s study compar-
ing low- vs. high-dose and intermittent vs. continuous
administration of IV AA in septic patients, bolus dosing
provided rapid plasma peak concentrations and continu-
ous dosing was effective in achieving high steady-state
concentrations [20]. For TBI patients in an ICU environ-
ment, both regimens of administration would be feasible.
Conclusion
Inflammatory processes, ROS, and endothelial dysfunc-
tion are well-established contributors to secondary brain
injury. The promising results achieved with antioxidants
and free radical scavengers in animal studies are in stark
contrast to disappointing clinical results. Based on its
mechanisms of action, animal data, and clinical results
in critical illness, high-dose AA has exceptional poten-
tial to be an effective treatment strategy in the acute
phase of TBI. It may be able to mitigate secondary brain
injury due to its antioxidant, anti-inflammatory, and cell
membrane-stabilizing properties, while the low adverse
effect and cost profile of AA make it well suited for clini-
cal studies in patients with TBI. A key challenge will be
to identify the ideal TBI patient population that is most
likely to benefit from this treatment strategy. Based on
the existing data from related fields, patients with moder-
ate to severe TBI, significant brain edema with elevated
intracranial pressure, and the older adult population may
represent ideal patient groups for high-dose IV AA in the
acute setting. Clinical trials in such high-risk populations,
rather than a more heterogenous patient group with TBI,
may be the key to translating the promising animal data
into actual improved patient outcomes. In summary, the
existing ample animal and limited clinical data suggest
that for the right patient population and at the appropri-
ate dose, high-dose IV AA can benefit patients with TBI.
Author details
1
 Division of Acute Care Surgical Services, Department of Surgery, Virginia
Commonwealth University School of Medicine, Richmond, USA. 2 Department
of Neurology, Wake Forest School of Medicine, Winston‑Salem, USA. 3 Depart-
ment of Pharmacotherapy and Outcomes Sciences, Virginia Commonwealth
University School of Pharmacy, Richmond, USA. 4 Division of Critical Care,
Department of Anesthesiology, Virginia Commonwealth University School
of Medicine, Richmond, USA. 5 Department of Neurosurgery, Virginia Com-
monwealth University School of Medicine, Richmond, USA. 6 Department
of Biostatistics, Virginia Commonwealth University, Richmond, USA.
Author Contributions
This manuscript complies with all instructions to authors. Authorship require-
ments have been met by all authors, and the final manuscript was approved
by all co-authors.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations.
References
1. Taylor CA, Bell JM, Breiding MJ, Xu L. Traumatic brain injury-related emer-
gency department visits, hospitalizations, and deaths—United States,
2007 and 2013. MMWR Surveill Summ. 2017;66(9):1–16.
2. Dearden NM. Mechanisms and prevention of secondary brain damage
during intensive care. Clin Neuropathol. 1998;17(4):221–8.
3. Jones PA, Andrews PJ, Midgley S, et al. Measuring the burden of second-
ary insults in head-injured patients during intensive care. J Neurosurg
Anesthesiol. 1994;6(1):4–14.
4. Lok J, Leung W, Murphy S, Butler W, Noviski N, Lo EH. Intracranial hemor-
rhage: mechanisms of secondary brain injury. Acta Neurochir Suppl.
2011;111:63–9.
5. Ikeda Y, Long DM. The molecular basis of brain injury and brain edema:
the role of oxygen free radicals. Neurosurgery. 1990;27(1):1–11.
6. Hall E, Braughler J. Central nervous system trauma and stroke: II. Physi-
ological and pharmacological evidence for involvement of oxygen
radicals and lipid peroxidation. Free Rad Biol Med. 1989;6(3):303–13.
7. Brau RH, García-Castiñeiras S, Rifkinson N. Cerebrospinal fluid ascorbic
acid levels in neurological disorders. Neurosurgery. 1984;14(2):142–6.
8. Tyurin VA, Tyurina YY, Borisenko GG, et al. Oxidative stress following trau-
matic brain injury in rats: quantitation of biomarkers and detection of free
radical intermediates. J Neurochem. 2002;75(5):2178–89.
9. Kontos HA, Povlishock JT. Oxygen radicals in brain injury. Central Nervous
System Trauma. 1986;3(4):257–63.
10. Povlishock JT, Kontos HA. The role of oxygen radicals in the pathobiology
of traumatic brain injury. Hum Cell. 1992;5(4):345–53.
11. Hutchinson PJ, Kolias AG, Timofeev IS, et al. Trial of decompressive
craniectomy for traumatic intracranial hypertension. N Engl J Med.
2016;375(12):1119–30.
12. Andrews PJD, Sinclair HL, Rodriguez A, et al. Hypothermia for intrac-
ranial hypertension after traumatic brain injury. N Engl J Med.
2015;373(25):2403–12.
13. DePhillipo NN, Aman ZS, Kennedy MI, Begley JP, Moatshe G, LaPrade RF.
Efficacy of vitamin C supplementation on collagen synthesis and oxida-
tive stress after musculoskeletal injuries: a systematic review. Orthop J
Sports Med. 2018;6(10):2325967118804544.
14. Biesalski HK, McGregor GP. Antioxidant therapy in critical care–is
the microcirculation the primary target? Crit Care Med. 2007;35(9
Suppl):S577–583.
15. Ellis GR, Anderson RA, Lang D, et al. Neutrophil superoxide anion–gen-
erating capacity, endothelial function and oxidative stress in chronic
heart failure: effects of short- and long-term vitamin C therapy. J Am Coll
Cardiol. 2000;36(5):1474–82.
16. Vanek VW, Borum P, Buchman A, et al. A.S.P.E.N. position paper: recom-
mendations for changes in commercially available parenteral multivita-
min and multi-trace element products. Nutr Clin Pract. 2012;27(4):440–91.
17. Levine M, Conry-Cantilena C, Wang Y, et al. Vitamin C pharmacokinetics in
healthy volunteers: evidence for a recommended dietary allowance. Proc
Natl Acad Sci USA. 1996;93(8):3704–9.
18. Berger MM. Vitamin C requirements in parenteral nutrition. Gastroenterol-
ogy. 2009;137(5 Suppl):S70–78.
19. Long CL, Maull KI, Krishnan RS, et al. Ascorbic acid dynamics in the seri-
ously ill and injured. J Surg Res. 2003;109(2):144–8.
20. de Grooth H-J, Manubulu-Choo W-P, Zandvliet AS, et al. Vitamin C
pharmacokinetics in critically Ill patients: a randomized trial of four IV
regimens. Chest. 2018;153(6):1368–77.
21. Levine M, Rumsey SC, Daruwala R, Park JB, Wang Y. Criteria and recom-
mendations for vitamin C intake. JAMA. 1999;281(15):1415–23.
22. Padayatty SJ, Sun H, Wang Y, et al. Vitamin C pharmacokinetics: implica-
tions for oral and intravenous use. Ann Intern Med. 2004;140(7):533–7.
23. Fowler AA, Syed AA, Knowlson S, et al. Phase I safety trial of intravenous
ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12:32.
24. Jackson TS, Xu A, Vita JA, Keaney JF. Ascorbate prevents the interaction
of superoxide and nitric oxide only at very high physiological concentra-
tions. Circ Res. 1998;83(9):916–22.
25. May JM. Vitamin C transport and its role in the central nervous system.
Subcell Biochem. 2012;56:85–103.
26. Harrison FE, May JM. Vitamin C function in the brain: vital role of the
ascorbate transporter SVCT2. Free Radic Biol Med. 2009;46(6):719–30.
27. Buehner M, Pamplin J, Studer L, et al. Oxalate nephropathy after continu-
ous infusion of high-dose vitamin c as an adjunct to burn resuscitation. J
Burn Care Res. 2016;37(4):e374–379.
28. Muhlhofer A, Mrosek S, Schlegel B, et al. High-dose intravenous vitamin C
is not associated with an increase of pro-oxidative biomarkers. Eur J Clin
Nutr. 2004;58(8):1151–8.
29. Nathens AB, Neff MJ, Jurkovich GJ, et al. Randomized, prospective trial of
antioxidant supplementation in critically ill surgical patients. Ann Surg.
2002;236(6):814–22.
30. Stephenson CM, Levin RD, Spector T, Lis CG. Phase I clinical trial to evalu-
ate the safety, tolerability, and pharmacokinetics of high-dose intrave-
nous ascorbic acid in patients with advanced cancer. Cancer Chemother
Pharmacol. 2013;72(1):139–46.
31. Hoffer LJ, Levine M, Assouline S, et al. Phase I clinical trial of i.v. ascorbic
acid in advanced malignancy. Ann Oncol. 2008;19(11):1969–74.
32. Monti DA, Mitchell E, Bazzan AJ, et al. Phase I evaluation of intravenous
ascorbic acid in combination with gemcitabine and erlotinib in patients
with metastatic pancreatic cancer. PLoS ONE. 2012;7(1):e29794.
33. Carr AC, Rosengrave PC, Bayer S, Chambers S, Mehrtens J, Shaw GM.
Hypovitaminosis C and vitamin C deficiency in critically ill patients
despite recommended enteral and parenteral intakes. Crit Care.
2017;21(1):300.
34. Polidori MC, Mecocci P, Frei B. Plasma vitamin C levels are decreased and
correlated with brain damage in patients with intracranial hemorrhage or
head trauma. Stroke. 2001;32(4):898–902.
35. Luo M, Fernandez-Estivariz C, Jones DP, et al. Depletion of plasma antioxi-
dants in surgical intensive care unit patients requiring parenteral feeding:
effects of parenteral nutrition with or without alanyl-glutamine dipeptide
supplementation. Nutrition. 2008;24(1):37–44.
36. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone,
vitamin C, and thiamine for the treatment of severe sepsis and septic
shock: a retrospective before-after study. Chest. 2017;151(6):1229–388.
37. Reynolds PS, Fisher BJ, McCarter J, et al. Interventional vitamin C: A
strategy for attenuation of coagulopathy and inflammation in a swine
multiple injuries model. J Trauma Acute Care Surg. 2018;85(1S Suppl
2):S57–S67.
38. Sanford K, Fisher BJ, Fowler E, Fowler AA, Natarajan R. Attenuation of
red blood cell storage lesions with vitamin C. Antioxidants (Basel).
2017;6(3):E55.
39. Mohammed BM, Fisher BJ, Kraskauskas D, et al. Vitamin C promotes
wound healing through novel pleiotropic mechanisms. Int Wound J.
2016;13(4):572–84.
40. Barichello T, Machado RA, Constantino L, et al. Antioxidant treatment
prevented late memory impairment in an animal model of sepsis. Crit
Care Med. 2007;35(9):2186–90.
41. Haywood-Watson RJ, Holcomb JB, Gonzalez EA, et al. Modulation of
syndecan-1 shedding after hemorrhagic shock and resuscitation. PLoS
ONE. 2011;6(8):e23530.
42. Johansson PI, Henriksen HH, Stensballe J, et al. Traumatic endotheliopa-
thy: a prospective observational study of 424 severely injured patients.
Ann Surg. 2017;265(3):597–603.
43. Wei S, Gonzalez Rodriguez E, Chang R, et al. Elevated syndecan-1 after
trauma and risk of sepsis: a secondary analysis of patients from the
pragmatic, randomized optimal platelet and plasma ratios (PROPPR) Trial.
J Am Coll Surg. 2018;227(6):587–95.
44. Fisher BJ, Seropian IM, Kraskauskas D, et al. Ascorbic acid attenu-
ates lipopolysaccharide-induced acute lung injury. Crit Care Med.
2011;39(6):1454–60.
45. Fisher BJ, Kraskauskas D, Martin EJ, et al. Mechanisms of attenuation
of abdominal sepsis induced acute lung injury by ascorbic acid. Am J
Physiol Lung Cell Mol Physiol. 2012;303(1):L20–32.
 46. Berger MM, Soguel L, Shenkin A, et al. Influence of early antioxidant sup-
plements on clinical evolution and organ function in critically ill cardiac
surgery, major trauma, and subarachnoid hemorrhage patients. Crit Care.
2008;12(4):R101.
47. Tanaka H, Matsuda T, Miyagantani Y, Yukioka T, Matsuda H, Shimazaki
S. Reduction of resuscitation fluid volumes in severely burned patients
using ascorbic acid administration: a randomized, prospective study. Arch
Surg. 2000;135(3):326–31.
48. Dubick MA, Williams C, Elgjo GI, Kramer GC. High-dose vitamin C infusion
reduces fluid requirements in the resuscitation of burn-injured sheep.
Shock. 2005;24(2):139–44.
49. Barbosa E, Faintuch J, Machado Moreira EA, et al. Supplementation of
vitamin E, vitamin C, and zinc attenuates oxidative stress in burned chil-
dren: a randomized, double-blind, placebo-controlled pilot study. J Burn
Care Res. 2009;30(5):859–66.
50. Kochanek PM, Dixon CE, Shellington DK, et al. Screening of biochemical
and molecular mechanisms of secondary injury and repair in the brain
after experimental blast-induced traumatic brain injury in rats. J Neuro-
trauma. 2013;30(11):920–37.
51. Arun P, Rittase WB, Wilder DM, Wang Y, Gist ID, Long JB. Defective methio-
nine metabolism in the brain after repeated blast exposures might
contribute to increased oxidative stress. Neurochem Int. 2018;112:234–8.
52. Huang J, Agus DB, Winfree CJ, et al. Dehydroascorbic acid, a blood-brain
barrier transportable form of vitamin C, mediates potent cerebroprotec-
tion in experimental stroke. Proc Natl Acad Sci USA. 2001;98(20):11720–4.
53. Mack WJ, Mocco J, Ducruet AF, et al. A cerebroprotective dose of intrave-
nous citrate/sorbitol-stabilized dehydroascorbic acid is correlated with
increased cerebral ascorbic acid and inhibited lipid peroxidation after
murine reperfused stroke. Neurosurgery. 2006;59(2):383–8 (discussion
383–388).
54. Ishaq GM, Saidu Y, Bilbis LS, Muhammad SA, Jinjir N, Shehu BB. Effects of
α-tocopherol and ascorbic acid in the severity and management of trau-
matic brain injury in albino rats. J Neurosci Rural Pract. 2013;4(3):292–7.
55. Yan M, Yang M, Shao W, et al. High-dose ascorbic acid administration
improves functional recovery in rats with spinal cord contusion injury.
Spinal cord. 2014;52(11):803–8.
56. Sajja RK, Prasad S, Tang S, Kaisar MA, Cucullo L. Blood-brain barrier disrup-
tion in diabetic mice is linked to Nrf2 signaling deficits: Role of ABCB10?
Neurosci Lett. 2017;653:152–8.
57. Zhao J, Moore AN, Redell JB, Dash PK. Enhancing expression of Nrf2-
driven genes protects the blood brain barrier after brain injury. J Neuro-
sci. 2007;27(38):10240–8.
58. Kelly PJ, Morrow JD, Ning M, et al. Oxidative stress and matrix metallopro-
teinase-9 in acute ischemic stroke: the Biomarker Evaluation for Antioxi-
dant Therapies in Stroke (BEAT-Stroke) study. Stroke. 2008;39(1):100–4.
59. Allahtavakoli M, Amin F, Esmaeeli-Nadimi A, Shamsizadeh A, Kazemi-
Arababadi M, Kennedy D. Ascorbic acid reduces the adverse effects of
delayed administration of tissue plasminogen activator in a rat stroke
model. Basic Clin Pharmacol Toxicol. 2015;117(5):335–9.
60. Guo M, Cox B, Mahale S, et al. Pre-ischemic exercise reduces matrix metal-
loproteinase-9 expression and ameliorates blood-brain barrier dysfunc-
tion in stroke. Neuroscience. 2008;151(2):340–51.
61. Lin J-L, Huang Y-H, Shen Y-C, Huang H-C, Liu P-H. Ascorbic acid prevents
blood-brain barrier disruption and sensory deficit caused by sustained
compression of primary somatosensory cortex. J Cereb Blood Flow
Metab. 2010;30(6):1121–36.
62. Smith SL, Andrus PK, Zhang JR, Hall ED. Direct measurement of hydroxyl
radicals, lipid peroxidation, and blood-brain barrier disruption follow-
ing unilateral cortical impact head injury in the rat. J Neurotrauma.
1994;11(4):393–404.
63. Vagnozzi R, Marmarou A, Tavazzi B, et al. Changes of cerebral energy
metabolism and lipid peroxidation in rats leading to mitochondrial
dysfunction after diffuse brain injury. J Neurotrauma. 1999;16(10):903–13.
64. Putzu A, Daems A-M, Lopez-Delgado JC, Giordano VF, Landoni G. The
effect of vitamin C on clinical outcome in critically ill patients: a system-
atic review with meta-analysis of randomized controlled trials. Crit Care
Med. 2019;47(6):774–83.
65. Maas AIR, Murray G, Henney H, et al. Efficacy and safety of dexanabinol in
severe traumatic brain injury: results of a phase III randomised, placebo-
controlled, clinical trial. Lancet Neurol. 2006;5(1):38–45.
66. Marshall LF, Maas AI, Marshall SB, et al. A multicenter trial on the
efficacy of using tirilazad mesylate in cases of head injury. J Neurosurg.
1998;89(4):519–25.
67. Muizelaar JP, Marmarou A, Young HF, et al. Improving the outcome of
severe head injury with the oxygen radical scavenger polyethylene
glycol-conjugated superoxide dismutase: a phase II trial. J Neurosurg.
1993;78(3):375–82.
68. Wright DW, Yeatts SD, Silbergleit R, et al. Very early administra-
tion of progesterone for acute traumatic brain injury. N Engl J Med.
2014;371(26):2457–66.
69. Razmkon A, Sadidi A, Sherafat-Kazemzadeh E, et al. Administration of vita-
min C and vitamin E in severe head injury: a randomized double-blind
controlled trial. Clin Neurosurg. 2011;58(Journal Article):133–7.
70. Siqueira IR, Elsner VR, Leite MC, et al. Ascorbate uptake is decreased in the
hippocampus of ageing rats. Neurochem Int. 2011;58(4):527–32.
71. Moor E, Shohami E, Kanevsky E, Grigoriadis N, Symeonidou C, Kohen R.
Impairment of the ability of the injured aged brain in elevating urate and
ascorbate. Exp Gerontol. 2006;41(3):303–11.
72. Carr A, Wohlrab C, Young P, Bellomo R. Stability of intravenous vitamin C
solutions: a technical report. Crit Care Resusc. 2018;20(3):180–1.
73. Wilson JX, Jaworski EM, Kulaga A, Dixon SJ. Substrate regula-
tion of ascorbate transport activity in astrocytes. Neurochem Res.
1990;15(10):1037–43.
74. Vera JC, Rivas CI, Fischbarg J, Golde DW. Mammalian facilitative hexose
transporters mediate the transport of dehydroascorbic acid. Nature.
1993;364(6432):79–82.